Acute Interstitial Nephritis and Oxalate Nephropathy After Rapid Pasireotide Response in Treatment-resistant Acromegaly.

We report a case of interstitial nephritis, likely secondary to oxalate nephropathy, due to the development of pancreatic exocrine dysfunction after commencement of pasireotide for acromegaly. Pasireotide is known to impair insulin secretion but can also impair pancreatic exocrine function, hypothezised to result from high-affinity binding of somatostatin receptors 1, 2, 3, and 5. This has been an advantage in postoperative tissue anastomoses after pancreatic surgery, but exocrine insufficiency has not been reported when used for the treatment of acromegaly. A 73-year-old woman, diagnosed with acromegaly, was unable to achieve biochemical control despite 2 surgical resections of an invasive mammosomatotroph pituitary tumor and treatment with cabergoline and maximal-dose lanreotide. The tumor expressed somatostatin receptor type 5 but not somatostatin receptor type 2, predicting good response from pasireotide, which was commenced at 40 mg every 4 weeks. IGF-1 rapidly normalized, but the patient presented with nausea, anorexia, and acute kidney injury. Renal biopsy revealed acute-on-chronic interstitial nephritis, with numerous oxalate crystals. Increased fecal fat globules were noted on fat stain (3+), supporting malabsorption as an etiology of secondary enteric hyperoxaluria. Renal function recovered to near baseline over months following pasireotide withdrawal and high-dose glucocorticoids.

Inter-rater concordance of basal cell carcinoma subtypes: influences on reporting format and opportunities for further classification modifications.

Diagnosis of basal cell carcinoma (BCC) higher risk subtypes influences management strategies because of their propensity to recur locally. Subtyping is prone to inter-observer variability, and subtyping definitions are inconsistently applied. This study sought to compare the interobserver reproducibility of individual BCC subtypes using the 4th edition World Health Organization (WHO) Classification of Skin Tumours (CoST) definitions, with classification into lower and higher risk histological subtype groups. Ninety-one BCC cases were rated by seven pathologists, noting the presence of BCC subtype(s), and providing a higher or lower risk subtype grouping per case. Raters were provided with definitions as per the 4th edition WHO CoST for 10 listed BCC subtypes. Surgical specimen type was noted. Subgroup analysis was performed to exclude cases when the tumour deep front was not well visualised, or there was tangential sectioning (n = 6). Light's kappa was used to assess inter-rater reliability. From the total group (n = 91), five BCC subtypes showed a sufficient number of ratings for computing a κ statistic. From these five subtypes, superficial subtype showed substantial inter-rater agreement (κ = 0.64), and the other four subtypes showed moderate inter-rater agreement [nodular (κ = 0.45), sclerosing/morphoeic (κ = 0.45), infiltrating (κ = 0.49) and micronodular (κ = 0.57)]. Two-tiered rating into either higher or lower risk subtype showed substantial inter-rater agreement (κ = 0.72). Our results suggest a need to more precisely define BCC subtypes. We suggest reporting BCC subtype using a two-tiered risk grouping, followed by specific subtypes present. Further studies examining the inter-rater reliability of less common BCC subtypes are required.

Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets.

Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3­kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.

Regression in cutaneous melanoma: histological assessment, immune mechanisms and clinical implications.

Tumour regression is an immunologically driven process that results in complete or partial disappearance of tumour cells. This can be observed in histological sections as replacement of tumour cells with fibrosis, angiogenesis, and a variable inflammatory infiltrate. In primary cutaneous melanoma, the prognostic significance of regression has been debated for decades, in part because inconsistent histological criteria are used in prognostication studies. It is broadly accepted that CD8+ T lymphocytes are the primary effectors of the anti-tumour response, but the interplay between melanoma and the immune system is complex, dynamic, and incompletely understood. Sustained progress in unravelling the pathogenesis of melanoma regression has led to the identification of therapeutic targets, culminating in the development of immune checkpoint inhibitors for the management of advanced disease. Modern techniques allow for high-resolution spatial analyses of the tumour microenvironment. Such studies may lead to better understanding of the immune drivers of melanoma regression, thereby facilitating the search for new prognostic and predictive biomarkers to assist clinical decision-making.

Histological regression in melanoma: impact on sentinel lymph node status and survival.

Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33; 95% C.I. 0.20-0.52; p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59-71%), MSS (85%, 95% C.I. 81-89%), and RFS (60%, 95% C.I. 54-66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69; 95% C.I. 0.51-0.94; p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71; 95% C.I. 0.58-0.85; p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.

Association of Histologic Regression With a Favorable Outcome in Patients With Stage 1 and Stage 2 Cutaneous Melanoma.

Importance: Although regression is commonly observed in cutaneous melanoma, it is uncertain whether it is associated with patient prognosis. Objective: To determine whether histologically confirmed regression was associated with better or worse survival in patients with primary cutaneous melanoma. Design, Setting, and Participants: This cohort study analyzed data from 2 large cohorts of adults (one in the Netherlands and the other in Australia) with histologically proven, stage 1 and 2 primary, invasive cutaneous melanoma with known regression status treated between 2000 and 2014, with median follow-up times of 4.5 and 11.1 years for the Dutch and Australian cohorts, respectively. For the Dutch patients, population-based data from PALGA, the Dutch Pathology Registry, were used, and follow-up data were retrieved from the Netherlands Cancer Registry. For the Australian patients, data from the database of a large, specialized melanoma treatment center were used. Main Outcomes and Measures: Multivariable Cox proportional hazards analyses were performed per cohort to assess recurrence-free survival (RFS) and overall survival (OS), and subgroup analyses according to Breslow thickness category and melanoma subtype were performed. Results: A total of 17 271 Dutch patients and 4980 Australian patients were included. In both cohorts, survival outcomes were better for patients with disease regression. For Dutch patients, the hazard ratio (HR) for those with disease regression was 0.55 (95% CI, 0.48-0.63; P < .001) for RFS and 0.87 (95% CI, 0.79-0.96; P = .004) for OS; for the Australian patients, the HR was 0.61 (95% CI, 0.52-0.72; P < .001) for RFS and 0.73 (95% CI, 0.64-0.84; P < .001) for OS. Subgroup analyses showed that the presence of regression improved RFS within thin and intermediate Breslow thickness melanomas in both cohorts. For patients with superficial spreading melanoma (SSM) subtype, regression improved RFS and OS in both cohorts. For Dutch patients with SSM, the HR for those with disease regression was 0.54 (95% CI, 0.46-0.63; P < .001) for RFS and 0.86 (95% CI, 0.76-0.96; P = .009) for OS; for the Australian patients with SSM, the HR was 0.67 (95% CI, 0.52-0.85; P = .001) for RFS and 0.72 (95% CI, 0.59-0.88; P = .001) for OS. Conclusions and Relevance: In 2 large patient cohorts from 2 different continents, regression was a favorable prognostic factor for patients with stage 1 and 2 melanomas, especially in those with thin and intermediate thickness tumors and those with SSM subtype.

A Rare Case of Duodenal Adenocarcinoma Presenting as a Subepithelial Lesion in a Patient Undergoing Investigation for Iron Deficiency Anaemia.

INTRODUCTION: Adenocarcinomas account for approximately 40% of small bowel cancers. They are typically mucosal lesions with distinctive features on endoscopy. We describe a rare case of duodenal adenocarcinoma presenting as a subepithelial lesion which posed a diagnostic challenge. CASE: An 85-year-old male patient presented for investigation of iron deficiency anaemia. Initial upper endoscopy found a subepithelial duodenal lesion with central depression but otherwise normal appearing mucosa. Superficial biopsies of the duodenal lesion were unremarkable. Subsequent antegrade single balloon enteroscopy revealed active bleeding from the lesion which was refractory to endoscopic treatment. A complete local excision of the lesion via laparotomy was necessary to achieve haemostasis. Histopathology from the lesion showed a moderately differentiated duodenal adenocarcinoma with invasion into the submucosa but no evidence of lymphovascular spread. CONCLUSION: Duodenal adenocarcinomas are rare gastrointestinal tumours associated with a poor prognosis. This case report outlines a rare presentation of duodenal adenocarcinoma and highlights the importance of judicious assessment of lesions found on endoscopy. Advances in endoscopic diagnostic modalities could facilitate early diagnosis and improve therapeutic outcomes.

Breslow Thickness Measurements of Melanomas Around American Joint Committee on Cancer Staging Cut-Off Points: Imprecision and Terminal Digit Bias Have Important Implications for Staging and Patient Management.

BACKGROUND: Breslow thickness is the most important prognostic factor in patients with clinically localized primary cutaneous melanomas, and its accuracy has important implications for staging and management. A review of the Melanoma Institute Australia database and population-based data for the state of New South Wales, Australia, found an unexpectedly large number of melanomas reported as being exactly 1.0 mm thick. We sought to determine possible causes for this biologically implausible finding. METHODS: The tumor thickness of 125 invasive cutaneous melanomas with a recorded Breslow thickness of 0.9-1.1 mm was remeasured and recorded by two pathologists. RESULTS: Concordance of measurements between the two pathologists was high (intraclass correlation coefficient 0.816, 95 % CI 0.733-0.873). The original measurements showed clustering at 0.9, 1.0, and 1.1 mm, whereas the review measurements did not. The original measurements staged 84 cases (72 %) as T1 and 33 (28 %) as T2, while the reviewed measurements staged 58 cases (50 %) as T1 and 59 (50 %) as T2 (p < 0.001). CONCLUSIONS: Our study demonstrated imprecision in Breslow thickness measurements and its significant impact on staging. Two potential sources of imprecision are failure to follow standardized thickness measurement guidelines and the phenomenon of terminal digit bias, not previously identified as a problem in this field. Educating pathologists about this phenomenon and the importance of utilizing ocular micrometers may improve the precision of melanoma thickness measurements around critical staging cut-off points. Clinicians must also be educated to appreciate that there is an inevitable margin of error with Breslow thickness measurements that should be considered when making management decisions.

Perineural invasion in oral squamous cell carcinoma: quantitative subcategorisation of perineural invasion and prognostication.

BACKGROUND: Evidence regarding the prognostic value of perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) and whether PNI alone warrants consideration of adjuvant therapy is controversial. We evaluated whether histopathological sub-categorization of PNI improves risk stratification. METHODS: PNI was evaluated for nerve size, number of foci, and distance from the tumor in 318 OSCC patients. Univariable and multivariable analyses were performed, with local failure (LF) and disease-specific survival (DSS) as the primary endpoints. RESULTS: PNI did not influence prognosis when classified as absent versus present. In contrast, multifocal PNI was associated with LF (P = 0.049) and decreased DSS (P = 0.043) on multivariable analyses. The size of the involved nerve separated those with multifocal PNI into intermediate (<1 mm) and high-risk (≥1 mm) groups. Unifocal PNI and distance from the tumor did not influence prognosis. Multifocal PNI was associated with worse prognosis irrespective of post-operative radiotherapy (PORT). CONCLUSIONS: Multifocal PNI is associated with poor outcomes even with PORT suggesting consideration of therapeutic escalation, particularly with involved nerves ≥1 mm. Unifocal PNI did not affect prognosis even in the absence of PORT, which may not be required if this is the sole risk factor. Prospective validation and testing of these hypotheses is essential before implementation.

Synthesis, structure, and stability of the high-temperature 6H-type perovskite phase Ba(3)BaSb(2)O(9).

The structure of Ba(3)BaSb(2)O(9) is reported for the first time as a high-temperature phase with an ideal hexagonal BaTiO(3)-type structure (space group P6(3)/mmc) and Rietveld-refined against high-temperature synchrotron X-ray powder diffraction data. The structure is remarkable for the extreme size difference between the pairs of face-sharing Sb(5+)O(6) octahedra (with mean Sb-O bonds of 1.99 Angstroms) and the single corner-sharing Ba(2+)O(6) octahedra (with mean Ba-O bonds of 2.46 Angstrom), which is greater than for any other reported 6H perovskite. This is consistent with the very different ionic radii of Sb(5+) (0.60 Angstroms) and Ba(2+) (1.35 Angstroms), and accounts for the instability of this phase at room temperature. The known symmetry-lowering modes of closely related 6H perovskites such as Ba(3)SrNb(2)O(9) and Ba(3)SrTa(2)O(9) are considered, but found not to account for the behaviour of Ba(3)BaSb(2)O(9) on cooling from high temperatures.